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Contribution to the understanding of radionuclide therapy with 177Lu-DOTATATE: investigation of new potential indications, drug combinations and the underlying radiobiology

par Delbart, Wendy
Président du jury Lybaert, Pascale
Promoteur Flamen, Patrick
Co-Promoteur Wimana, Zéna
Publication Non publié, 2023-06-05

Thèse de doctorat

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Résumé :

The mechanism of action of peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE has not fully been elucidated yet nor its specific radiobiology. The latter has been mainly extrapolated from external beam radiation therapy (EBRT) knowledge. The present work therefore focuses on the understanding of 177Lu-DOTATATE radiobiology and the investigation of new potential indications of PRRT beyond neuroendocrine tumours (NETs), with the ultimate goal of improving the clinical outcomes of patients. Initially, cellular characteristics predictive of 177Lu-DOTATATE sensitivity were investigated. In a panel of human cancer cell lines (gastroenteropancreatic adenocarcinoma, melanoma and multiple myeloma) expressing somatostatin receptors, we found that low antioxidant defenses, including glutathione (GSH), and low glucose metabolism were common traits among the cell lines that responded best to 177Lu-DOTATATE, namely multiple myeloma and melanoma.In a second step, the biological effects induced by PRRT and EBRT were compared and revealed common radiobiological mechanisms but to a different extent and/or with dissimilar kinetics. In particular, no marked early (within one hour) increase in DNA damage (double-strand breaks) was seen after PRRT in contrast to EBRT. The cytotoxic effect of DNA repair inhibition combined with EBRT was more potent than when combined with PRRT.Lastly, based on the aforementioned findings, we hypothesized that targeting the antioxidant defense system, rather than DNA repair mechanisms, may radiosensitize tumour cells to PRRT. Indeed, buthionine sulfoximine (BSO)-induced decreased GSH levels enhanced 177Lu-DOTATATE therapeutic effects in vitro and in a multiple myeloma xenograft mouse model.In conclusion, our study underlines the importance of antioxidant defenses in 177Lu-DOTATATE sensitivity. In addition, our results advocate for the undertaking of dedicated radionuclide therapy radiobiology studies owing to the radiobiological differences with EBRT. Furthermore, we provided preliminary PRRT data in melanoma and multiple myeloma, beyond its current indication in NETs.